T cells bearing invariant y5 T cell antigen receptors (TCR) localize to distinct epithelial sites in the adult mouse where they interact with non-classical antigen presenting cells such as epithelial cells. Many of these y8 T cell populations do not express traditional costimulatory molecules such as CD28 suggesting that they may rely on signals delivered through novel receptor-ligand interactions. We have identified AMIGA, a member of the junctional adhesion molecule family, as a costimulatory molecule for epithelial y8 T cells. AMIGA is expressed on all y5 T cells and in vitro mitogen activation leads to upregulated surface expression. Among lymphoid cells, AMIGA is preferentially expressed by y8 T cells although a small subpopulation of CD8+ ap T cells also express AMIGA after activation. Signals delivered through AMIGA costimulate skin and intestinal y5 T cell proliferation and cytokine release but not activation of any ap T cells or lymphoid y5 T cells. We will test the hypothesis that AMIGA expressed by epithelial y8 T cells binds to a ligand expressed on damaged epithelial cells and that interaction between this novel receptor-ligand pair delivers costimulatory signals to the y8T cell that are critical for participation in local immune responses including tissue homeostasis and repair. Together these studies should determine the roles of AMIGA in the activation and function of epithelial y8 T cells and may be applicable for manipulation of y8 T cell responses in epithelial disorders.